Ameliorant for blood lipid metabolism

ABSTRACT

The present invention is to provide an ameliorant for blood lipid metabolism which comprises as an active ingredient N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluorophenyl)-1-piperazinebutanamide or a pharmaceutically acceptable salt thereof, more particularly, to provide a hyperlipidemia inhibitor and an atherosclerosis inhibitor.

This application is a 371 of PCT/JP92/01173 Sep. 14, 1992.

TECHNICAL FIELD

The present invention relates to a useful and novel agent as a medicine. Particularly, the present invention relates to a novel use of a specific dibenzo[b,e]thiepine derivative. That is, the present invention relates to an ameliorant for blood lipid metabolism, which comprises as an active ingredient a dibenzob[b,e]thiepine derivative of the following structural formula (hereinafter, referred to as Compound A), or a pharmaceutically acceptable salt thereof, more particularly, the present invention relates to a hyperlipidemia inhibitor and an inhibitor of atherosclerosis in the aorta, and a method for ameliorating blood lipid metabolism. ##STR1##

It has been already disclosed in Japanese Patent Second Publication (Kokoku) No. 58341/1991 (U.S.Pat. No. 4,749,703) that Compound A of the present invention and salts thereof have a potent calcium antagonistic activity and are useful as a hypotensive agent. Besides, it has also been disclosed in Jpn. J. Pharmacol., 52 (suppl. 1), 212 (No. P067) (1990) that Compound A and salts thereof have α₁ -receptor blocking activity.

In Am. J. Cardiology 64, 129 l-134 l (1989), there is an introduction of many reports as to the hyperlipidemia inhibitory activity and the atherosclerosis inhibitory activity of various calcium antagonists, wherein it is described that the antagonists did not show any hyperlipidemia inhibitory activity in most of the reports and that as to atherosclerosis inhibitory activity the antagonists showed positive activity in some reports but did not in other reports.

Moreover, it is reported that diltiazem, which is a benzothiazepine derivative and a well known hypotensive agent having calcium antagonistic activity, shows the atherosclerosis inhibitory activity in rabbits [Lab. Invest., 49 (2), 154-158 (1983)], and on the contrary, there is a report of having no inhibitory activity [Atherosclerosis, 51, 343-344 (1984)].

Besides, it is reported that prazosin, which is a benzopyrimidine derivative being well known as a hypotensive agent having α₁ -receptor blocking activity, shows blood lipid decreasing activity in human being [Am. J. Medicine, 76 (suppl. 2A), 79-84 (1984)], and on the contrary, there is a report of having no blood lipid decreasing activity [Prog. Medicine 3, 1517-1525 (1983)].

DISCLOSURE OF INVENTION

The present inventors have found that the above Compound A shows the hyperlipidemia inhibitory activity as well as the atherosclerosis inhibitory activity at a dose effective for showing hypotensive activity, and that they are useful as an ameliorant for blood lipid metabolism, more particularly, as a hyperlipidemia inhibitor and atherosclerosis inhibitor, and have accomplished the present invention.

That is, an object of the present invention is to provide an ameliorant for blood lipid metabolism which comprises as an active ingredient Compound A or a pharmaceutically acceptable salt thereof. More particularly, the object of the present invention is to provide a hyperlipidemia inhibitor and atherosclerosis inhibitor.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the appearances of lipid deposition at the aortic inner wall. Each figure shows the appearances of lipid deposition, i.e. the appearances of plaque formation in the following groups, (a): the normal control group (normally fed);(b): the positive control group (fed with high fat feed); (c): maleate of Compound A-treated group; (d): the prazosin-treated group; and (e): the diltiazem-treated group.

BEST MODE FOR CARRYING OUT INVENTION

The present inventors have firstly found that the above mentioned Compound A and a pharmaceutically acceptable salt thereof inhibit the increase in blood lipid at a dose effective for showing hypotensive activity (hyperlipidemia inhibitory activity) as well as inhibit the lipid deposition at the aortic inner wall (atherosclerosis inhibitory activity), by which they are useful as an ameliorant for blood lipid metabolism, and have accomplished the present invention.

The pharmaceutically acceptable salt of Compound A of the present invention includes, for example, salts with an inorganic acid (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.) and salts with an organic acid (e.g. oxalate, maleate, fumarate, malate, citrate, benzoate, methanesulfonate, etc.). Among them, the maleate is more preferable. Besides, Compound A and a pharmaceutically acceptable salt thereof may be in the form of a hydrate or solvate, or in the form of optically active compound.

The safety of Compound A and a pharmaceutically acceptable salt thereof in the living body is already proved and confirmed, for example, the acute toxicity (LD₅₀) in oral administration of the maleate of Compound A in mice (Jcl. ICR) is more than 500 mg/kg, and no significant toxicity was observed in rats and beagles even by prolonged administration.

Compound A and a pharmaceutically acceptable salt thereof may easily be prepared according to the disclosure of U.S. Pat. No. 4,749,703, for example, according to the disclosure of Example 1 thereof.

The agent of the present invention may be administered either orally or parenterally such as intrarectally, but oral administration is preferable. The daily dosage of the present agent varies according to the administration routes and the conditions and ages of patients, but it is usually in the range of 0.01 to 5 mg of Compound A per 1 kg of body weight, preferably in the range of 0.1 to 3 mg of Compound A per 1 kg of body weight, more preferably in the range of 0.5 to 2 mg of Compound A per 1 kg of body weight, and the compound of the present invention is administered at one time, or dividedly for several times per day. At this dosage, Compound A and a pharmaceutically acceptable salt thereof show not only the ameliorating activity of blood lipid metabolism but also hypotensive activity.

The agent of the present invention may usually be in the form of tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections, suppositories, and the like. The carriers incorporated with these pharmaceutical forms may be any conventional ones which do not react with Compound A and a pharmaceutically acceptable salt thereof, for example, lactose, glucose, mannitol, dextrin, starch, white sugar, crystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), low-viscosity hydroxypropyl cellulose (HPC-L), hydroxypropyl methylcellulose (HPMC), light silicic anhydride, polyvinyl-pyrrolidone, talc, sorbitan fatty acid ester, macrogol, wax, water, and the like.

These pharmaceutical preparations may contain Compound A or a pharmaceutically acceptable salt thereof in an amount of more than 0.5%, preferably 1 to 85%, and may contain other pharmaceutically active compounds, if necessary.

The pharmacological activity of the present agent is illustrated by Experiment in comparison with diltiazem; a calcium antagonist, and prazosin; an α₁ -receptor blocking agent.

Experiment

In this experiment, male white Japanese rabbits (5 to 7 rabbits/group) were used. The high fat feed was prepared by adding 1% cholesterol and 6% coconut oil to the solid feed (Oriental Yeast Co., Ltd., RC-4). Each rabbit was fed with the high fat feed in an amount of 100 g every day, and two weeks later, the total plasma cholesterol of each rabbit was determined and confirmed to be more than 1000 mg/dl, and the rabbits were divided into two groups.

In one group, 0.5% tragacanth solution (vehicle, control) were administered to the rabbits, and in other groups, the maleate of Compound A, diltiazem or prazosin was administered orally once a day for 9 weeks. The dosages of the maleate of Compound A, diltiazem and prazosin were 30 mg/kg/day, 50 mg/kg/day and 3 mg/kg/day, respectively, and at these dosages, these compounds show hypotensive activity as well.

Separately, in the normal feed group, each rabbit was given normal solid feed (RC-4) (100 g/day) and a vehicle (tragacanth solution) orally.

Six, eight and nine weeks after the beginning of administration, the total cholesterol, free cholesterol and phospholipid in plasma were determined, and the results are shown in the following Tables 1 to 3.

Nine weeks after the beginning of administration, each rabbit was killed with bleeding under pentobarbital-anesthesia, and the aorta was taken out. The cholesterol amount in the aorta was determined, and the lipid deposition at the aortic inner wall was stained and the area of the stained parts was measured. The results are shown in the following Table 4 and FIG. 1.

                  TABLE 1                                                          ______________________________________                                         Cholesterol concentration in plasma                                                    Total cholesterol concentration in plasma                                      (mg/dl ± standard error)                                                    Test Period (weeks)                                                    Tested Groups                                                                            0         6         8        9                                       ______________________________________                                         Normal feed +                                                                             25 ± 2**                                                                              27 ± 4**                                                                              18 ± 2**                                                                             28 ±                                Vehicle                                4**                                     High fat feed +                                                                          1070 ± 139                                                                            2279 ± 289                                                                            1918 ± 227                                                                           2106 ±                               Vehicle                                320                                     High fat feed +                                                                          1161 ± 110                                                                            1595 ± 136                                                                             1074 ± 162*                                                                         1070 ±                               Compound                               171*                                    A***                                                                           High fat feed +                                                                          1127 ± 202                                                                            2297 ± 127                                                                            2106 ± 293                                                                           1626 ±                               diltiazem                              221                                     High fat feed +                                                                          1201 ± 45                                                                             3048 ± 236                                                                            2082 ± 194                                                                           1999 ±                               prazosin                               317                                     ______________________________________                                          *Significantly different from [High fat feed + Vehicle] group (p < 0.05)       **Significantly different from [High fat feed +  Vehicle] group (p < 0.01      ***The maleate of Compound A                                             

As shown in Table 1, the total cholesterol concentration was significantly decreased from 8 weeks after the beginning of administration in the maleate of Compound A-treated group. On the other hand, no decrease in the total cholesterol concentration in diltiazem-treated group and prazosin-treated group was observed even at 9 weeks after the beginning of administration.

                  TABLE 2                                                          ______________________________________                                         Free cholesterol concentration in plasma                                               Free cholesterol concentration in plasma                                       (mg/dl ± standard error)                                                    Test Period (weeks)                                                    Tested Groups                                                                            0         6         8       9                                        ______________________________________                                         Normal feed +                                                                              8 ± 1**                                                                              10 ± 1**                                                                               8 ± 1**                                                                            5 ±                                  Vehicle                               1**                                      High fat feed +                                                                          349 ± 38                                                                              746 ± 85                                                                              607 ± 79                                                                            672 ±                                 Vehicle                               140                                      High fat feed +                                                                          346 ± 34                                                                              503 ± 43                                                                               330 ± 56*                                                                          306 ±                                 Compound                              39*                                      A***                                                                           High fat feed +                                                                          318 ± 57                                                                              660 ± 42                                                                              673 ± 96                                                                            486 ±                                 diltiazem                             62                                       High fat feed +                                                                          368 ± 22                                                                              916 ± 69                                                                              740 ± 96                                                                            584 ±                                 prazosin                              94                                       ______________________________________                                          *Significantly different from [High fat feed + Vehicle] group (p < 0.05)       **Significantly different from [High fat feed + Vehicle] group (p < 0.01)      ***The maleate of Compound A                                             

As is shown in Table 2, the free cholesterol concentration was significantly decreased from 6 weeks after the beginning of the administration in the maleate of Compound A-treated group. On the other hand, no decrease in the free cholesterol concentration in diltiazem-treated group and prazosin-treated group was observed even at 9 weeks after the beginning of the administration.

                  TABLE 3                                                          ______________________________________                                         Phospholipid concentration in plasma                                                   Phospholipid concentration in plasma                                           (mg/dl ± standard error)                                                    Test Period (weeks)                                                    Tested Groups                                                                            0         6          8       9                                       ______________________________________                                         Normal feed +                                                                             54 ± 2**                                                                               46 ± 1**                                                                             103 ± 8**                                                                            49 ±                                Vehicle                                3**                                     High fat feed +                                                                          461 ± 52                                                                              1018 ± 98                                                                              774 ± 82                                                                            879 ±                                Vehicle                                144                                     High fat feed +                                                                          452 ± 42                                                                               678 ± 70*                                                                             529 ± 66*                                                                           489 ±                                Compound                               60*                                     A***                                                                           High fat feed +                                                                          454 ± 72                                                                               931 ± 50                                                                              825 ± 116                                                                           718 ±                                diltiazem                              76                                      High fat feed +                                                                          474 ± 22                                                                              1240 ± 94                                                                              937 ± 112                                                                           803 ±                                prazosin                               108                                     ______________________________________                                          *Significantly different from [High fat feed + Vehicle] group (p < 0.05)       **Significantly different from [High fat feed +  Vehicle] group (p < 0.01      ***The maleate of Compound A                                             

As is shown in Table 3, the phospholipid concentration was significantly decreased from 6 weeks after the beginning of the administration in the maleate of Compound A-treated group. On the other hand, no decrease in the phospholipid concentration in diltiazem-treated group and prazosin-treated group was observed even at 9 weeks after the beginning of the administration.

                  TABLE 4                                                          ______________________________________                                         Effects on atherosclerosis                                                                Cholesterol amount                                                                            Area of lipid                                                   in aortas      deposition at aortic                                 Tested Groups                                                                             (mg/kg of protein)                                                                            inner wall (%)****                                   ______________________________________                                         Normal feed +                                                                              19.4 ± 1.8**                                                                               0.0                                                 Vehicle                                                                        High fat feed +                                                                           373.4 ± 45.1                                                                               53.6                                                 Vehicle                                                                        High fat feed +                                                                           234.4 ± 39.4*                                                                              35.2                                                 Compound A***                                                                  High fat feed +                                                                           509.3 ± 240.1                                                                              45.2                                                 diltiazem                                                                      High fat feed +                                                                           372.8 ± 63.9                                                                               56.7                                                 prazosin                                                                       ______________________________________                                          *Significantly different from [High fat feed + Vehicle] group (p < 0.05)       **Significantly different from [High fat feed + Vehicle] group (p < 0.01)      ***The maleate of Compound A                                                   ****The percentage of lipid deposition area to the whole area of aortic        inner wall                                                               

As is shown in Table 4 and FIG. 1, the cholesterol amount in the aorta in [High fat feed+Vehicle] group was significantly increased as compared with that of [Normal Feed] group, and the area of lipid deposition at the aortic inner wall was almost 54% of the total area of the aortic inner wall. On the contrary, the cholesterol amount in the aorta in the maleate of Compound A-treated group was significantly decreased, and the area of lipid deposition was also decreased. On the other hand, neither the cholesterol amount in the aorta nor the area of lipid deposition at the aortic inner wall in the diltiazem-treated group and prazosin-treated group was not decreased at all.

From the above results, it is proved that Compound A and a pharmaceutically acceptable salt thereof have the hyperlipidemia inhibitory activity (Tables 1 to 3) and the atherosclerosis inhibitory activity (Table 4, FIG. 1), by which they are an excellent agent for ameliorating blood lipid metabolism.

EXAMPLES

The present invention is illustrated by Examples for preparing the pharmaceutical preparations.

Example 1

Preparation of Tablets

    ______________________________________                                         Formula;                                                                       ______________________________________                                         Maleate of Compound A                                                                               30     mg                                                 Lactose              55     mg                                                 L-HPC                30     mg                                                 HPC-L                3      mg                                                 Crystalline Cellulose                                                                               26     mg                                                 Talc                 5      mg                                                 Light silicic anhydride                                                                             1      mg                                                 Total                150    mg/tablet                                          ______________________________________                                    

Method;

The prescribed amounts of maleate of Compound A, lactose and L-HPC are combined, and the mixture is granulated by wet granulation. To the granules are added the remaining components, and the mixture is tabletted to give tablets.

Example 2

Preparation of powders

    ______________________________________                                         Formula;                                                                       ______________________________________                                         Maleate of Compound A  20     g                                                HPMC                   60     g                                                Lactose                760    g                                                L-HPC                  160    g                                                ______________________________________                                    

Method;

Maleate of Compound A and HPMC are dissolved in a mixture (2000 ml) of dichloromethane and ethanol (1:1), and the mixture is sprayed to the mixture of lactose and L-HPC by using a fluidized granulator, and the mixture is dried to give powders.

Industrial Applicability

The agent of the present invention is useful as an ameliorant for blood lipid metabolism, especially as a hyperlipidemia inhibitor and atherosclerosis inhibitor, in mammals including human beings. 

We claim:
 1. A method for ameliorating blood lipid metabolism in a mammal with a blood lipid metabolism disorder, which comprises administering to said mammal a therapeutically, effective amount of a compound having the structure ##STR2## or a pharmaceutically acceptable salt thereof.
 2. The method according to claim 1, which inhibits hyperlipidemia.
 3. The method according to claim 1, which inhibits atherosclerosis.
 4. A method for treating hyperlipidemia in a mammal in need of such treatment comprising administering to said mammal a hyperlipidemia inhibiting effective amount of a compound having the structure ##STR3## or a pharmaceutically acceptable salt thereof.
 5. The method according to claim 4 wherein the pharmaceutically acceptable salt of said compound is administered to the mammal.
 6. The method according to claim 5 wherein the pharmaceutically acceptable salt is the pharmaceutically acceptable acid addition salt of said compound.
 7. The method according to claim 6 wherein the pharmaceutically acceptable salt is the maleate of said compound.
 8. The method according to claim 4 wherein the mammal is a human being.
 9. A method for treating atherosclerosis in a mammal in need of such treatment comprising administering to said mammal an atherosclerosis inhibiting effective amount of a compound having the structure ##STR4## or a pharmaceutically acceptable salt thereof.
 10. The method according to claim 9 wherein the pharmaceutically acceptable salt of said compound is administered to the mammal.
 11. The method according to claim 10 wherein the pharmaceutically acceptable salt is the pharmaceutically acceptable acid addition salt of said compound.
 12. The method according to claim 11 wherein the pharmaceutically acceptable salt is the maleate of said compound.
 13. The method according to claim 9 wherein the mammal is a human being.
 14. The method according to claim 1 wherein the therapeutically effective amount is a hyperlipidemia inhibiting effective amount or atherosclerosis inhibiting effective amount.
 15. The method according to claim 1 wherein the pharmaceutically acceptable salt of said compound is administered to the mammal.
 16. The method according to claim 15 wherein the pharmaceutically acceptable salt is the pharmaceutically acceptable acid addition salt of said compound.
 17. The method according to claim 16 wherein the pharmaceutically acceptable salt is the maleate of said compound.
 18. The method according to claim 1 wherein the mammal is a human being. 